Chapter 49 Malaria

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Malaria is a major international health problem. As global travel increases, malaria is found with increasing frequency in areas in which malaria is not endemic. Human malaria is typically caused by four species of parasitic protozoa—Plasmodium falciparum, Plasmodium vivax, Plasmodium ovale, and Plasmodium malariae—that are transmitted by mosquitoes. Prevention of malaria infection through counseling, chemoprophylaxis, and personal protective measures can significantly reduce the risk of malaria morbidity in travelers. Because malaria infection can be life threatening, awareness of rapid diagnosis and management of this disease by health care providers are essential.

Epidemiology

Malaria is endemic throughout tropical areas of the world and is usually transmitted to humans through the bite of a female Anopheles mosquito (Figure 49-1, online). Nearly 48% of the world’s population live in malaria-endemic areas.²⁵ According to the World Health Organization (WHO), there were an estimated 243 million cases (5th to 95th percentiles, 190 to 311 million cases) of malaria worldwide in 2008, which resulted in an estimated 863,000 deaths (5th to 95th percentiles, 708 to 1.3 million deaths).⁶⁴ The majority of the cases occurred in the African region (89%).⁶⁴ Most malaria-related deaths occur among infants and young children. In Africa, malaria accounts for 20% of all childhood deaths. P. falciparum and P. malariae are found throughout malaria-endemic areas of the world, including Latin America, sub-Saharan Africa, Asia, and the South Pacific. P. vivax is endemic in Latin America, Asia, and the South Pacific, but uncommon in areas of sub-Saharan Africa. Both P. falciparum and P. vivax were historically endemic in temperate areas such as North America and Europe, and transmission still occurs rarely in these areas.³⁸ Specifically, in the United States, anopheline mosquitoes are present (at least seasonally) in all states except Hawaii. Low frequencies of P. ovale infection are prevalent in most malaria-endemic areas, especially in West Africa.

Figure 49-1 A, Malaria-endemic countries in the Western Hemisphere. B, Malaria-endemic countries in the Eastern Hemisphere.

(From the Centers for Disease Control and Prevention: CDC health information for international travel 2012: The yellow book, New York, 2012, Oxford University Press. http://wwwnc.cdc.gov/travel/yellowbook/2012/chapter-3-infectious-diseases-related-to-travel/malaria.htm. A from Map 3-09, http://wwwnc.cdc.gov/travel/pdf/yellowbook-2012-map3-9-malaria-endemic-countries-western-hemisphere.pdf.) B from Map 3-10, http://wwwnc.cdc.gov/travel/pdf/yellowbook-2012-map-03-10-malaria-endemic-countries-eastern-hemisphere.pdf.)

The risk of acquiring malaria is highest for travelers to sub-Saharan Africa and Oceania (i.e., Papua New Guinea, Vanuatu, and the Solomon Islands), intermediate in the Indian subcontinent and Haiti, and lowest (but still significant) in Southeast Asia and the Americas (Table 49-1).⁷ There can be variability in transmission within endemic areas based on season, altitude, and type of travel. For example, the risk of acquiring malaria is lower for a business traveler to a Southeast Asian city staying in an air-conditioned hotel than for a backpacker hiking and sleeping in tents in East Africa. Rates of malaria among U.S. civilians have been rising as travel to malaria-endemic areas increases.³² In 2009, there were 1484 cases of malaria in the United States reported to the Centers for Disease Control and Prevention (CDC).³² The majority were imported from malaria-endemic areas of Africa (73%) and Asia (14%) and caused by P. falciparum (46%).³² In addition, cases of malaria have been acquired in the United States, which indicates that transmission is possible in temperate areas where Anopheles mosquitoes are present.^16,³²

TABLE 49-1 Risk of Malaria by Region

Risk	Region
High	Sub-Saharan Africa, Papua New Guinea, the Solomon Islands, and Vanuatu
Intermediate	Indian subcontinent and Haiti
Low (but significant)	Southeast Asia, Central America, and South America

From the American Academy of Pediatrics: Malaria. In Pickering LK, Baker CJ, Long SS, et al, editors: Red Book: 2006 report of the Committee on Infectious Diseases, ed 27, Elk Grove Village, Ill, 2006, American Academy of Pediatrics, pp 435-441.

Parasite resistance to antimalarials has been increasing (Table 49-2).⁵⁶ In addition, P. falciparum is becoming resistant to other antimalarials, such as mefloquine, pyrimethamine–sulfadoxine, and halofantrine (Figure 49-2).⁷ Pyrimethamine–sulfadoxine resistance is common throughout Africa. Mefloquine resistance has been demonstrated in Burma (Myanmar), Thailand, Cambodia, Vietnam, and China.⁷ In Southeast Asia, partial resistance of P. falciparum to quinine or quinidine has also been reported. Areas with reports of chloroquine-resistant P. vivax include Indonesia, Papua New Guinea, the Solomon Islands, Vanuatu, Myanmar, India, Brazil, and Guyana.³ Chloroquine-resistant P. malariae has been described in Sumatra.³¹

TABLE 49-2 Antimalarial Drug Resistance in Malarial Parasites

Plasmodium Species	Drugs for Which Resistance is Established
P. falciparum	Chloroquine, mefloquine, pyrimethamine–sulfadoxine, and halofantrine; partial resistance to quinine and quinidine; resistance to multiple drugs
P. vivax	Chloroquine, pyrimethamine–sulfadoxine, and primaquine
P. ovale	None established
P. malariae	None established

FIGURE 49-2 Geographic distribution of mefloquine-resistant malaria.

(From the Centers for Disease Control and Prevention: CDC health information for international travel 2012: The yellow book, New York, 2010, Oxford University Press. From Map 3-11, http://wwwnc.cdc.gov/travel/pdf/yellowbook-2012-map3-11-distribution-mefloquine-resistant-malaria.pdf.)

Many genetic changes in human red blood cells occur in areas where malaria is or was historically endemic, which suggests that these polymorphisms have arisen to protect individuals from malaria. Sickle cell disease, thalassemia, glucose-6-phosphate dehydrogenase (G6PD) deficiency, and Southeast Asian ovalocytosis (including Gerbich negativity) have all been suggested to confer protection from falciparum malaria mortality.^42,⁵⁵ In sub-Saharan Africa, nearly 100% of the population is negative for the Duffy blood group and has absolute protection against P. vivax, which depends on the Duffy antigen as a receptor for invasion.³⁵

Malaria Parasite

Etiology

The malaria parasite is an intra-erythrocytic protozoan that is part of the Plasmodium genus. Plasmodium species infect mammals, birds, and reptiles. The four species that typically infect humans include P. falciparum, P. vivax, P. ovale, and P. malariae. The simian parasite P. knowlesi has been documented as a cause of severe infections and fatalities in Southeast Asia.¹⁷

Mosquito Vector

The female Anopheline mosquito is the arthropod vector for the malaria parasite (Figure 49-3). Of almost 430 Anopheles species, only 30 to 40 transmit malaria (Figure 49-4). These include Anopheles gambiae, Anopheles funestus, and Anopheles arabiensis in Africa; the Anopheles punctulatus group in Papua New Guinea; Anopheles culicifacies in India; Anopheles darlingi in South America; and Anopheles quadrimaculatus in North America.²⁹ The female mosquito’s proboscis pierces the skin of a person to obtain the blood meal necessary for her to produce eggs. Distinguishing features of Anopheles mosquitoes include sensory palps that are as long as the proboscis and discrete blocks of black and white scales on the wings.⁵ Both male and female Anopheles mosquitoes rest with their abdomens sticking up in the air as opposed to parallel to the surface on which they are resting.⁶

FIGURE 49-3 Female Anopheles gambiae mosquito feeding. Distinguishing features include sensory palps that are as long as the proboscis and discrete blocks of black and white scales on the wings. Both male and female Anopheles mosquitoes rest with their abdomens sticking up in the air.

(From the Centers for Disease Control and Prevention: Public Health Image Library. http://phil.cdc.gov/phil/home.asp. Left, image no. 1665; right, image no. 1664. Courtesy Dr. Jim Gathany and the Centers for Disease Control and Prevention.)

FIGURE 49-4 Global distribution of malaria vectors.

(From Kiszewski A, Mellinger A, Spielman A, et al: A global index representing the stability of malaria transmission, Am J Trop Med Hyg 70:486, 2004.)

Life Cycle

The life cycle of the malaria parasite involves both vertebrate and arthropod hosts (Figure 49-5). The asexual haploid form of the malaria parasite in the mosquito is the sporozoite. Transmission of 8 to 12 sporozoites usually occurs through the bite of a nocturnal-feeding female Anopheles mosquito (see Figure 49-3). Sporozoites then rapidly migrate through the bloodstream to the liver, where they mature and produce 10,000 to 30,000 merozoites per sporozoite. The merozoites are released into the bloodstream 8 to 25 days later to invade circulating erythrocytes (see Figure 49-5).²¹ A subset of P. vivax and P. ovale parasites may remain dormant as hypnozoites in the liver and emerge as merozoites months to years after the initial inoculation to establish blood-stage infection. Merozoites enter red blood cells rapidly through specific erythrocyte receptors, many of which are yet undefined. P. falciparum has several invasion pathways, including glycophorins A and C, whereas P. vivax depends solely on the Duffy antigen for erythrocyte invasion.⁶⁵

FIGURE 49-5 Malarial parasite life cycle. During the malarial parasite life cycle, sporozoites are transmitted through the bite of a nocturnal-feeding female Anopheles mosquito (A). Sporozoites then migrate to the liver (B) and mature to merozoites (C). A subset of P. vivax and P. ovale parasites remains dormant as hypnozoites emerging months to years after the initial infection to cause disease. Eight to 25 days after the initial infection, 10,000 to 30,000 merozoites are released to invade erythrocytes (D). Asexual parasites mature in 48 to 72 hours, each releasing 6 to 24 merozoites to invade more erythrocytes (E). Some parasites develop into gametocytes (sexual stages), which are taken up during a mosquito blood meal. Diploid zygotes form ookinetes and develop into haploid sporozoites (F). The sporozoites migrate to the mosquito salivary gland and continue the life cycle in humans with the next blood meal.

(Courtesy Sheral S. Patel, with permission.)

In the red blood cell, the asexual parasites consume hemoglobin and enlarge from the ring forms to become trophozoites and then schizonts. As the schizonts mature through multiple nuclear divisions, the red blood cell bursts and releases 6 to 24 merozoites to invade additional circulating erythrocytes.⁴ The blood-stage cycle takes place over 48 to 72 hours. Some parasites develop into gametocytes (the sexual stage), which can infect mosquitoes when taken up during a feeding. After being ingested by an Anopheles mosquito, diploid zygotes are formed. Zygotes mature into ookinetes in the mosquito midgut.⁴⁷ The resulting oocyst expands through meiotic reduction division within 7 to 10 days and releases sporozoites that localize through the hemolymph to the salivary gland of the mosquito.⁴ The sporozoites are subsequently transmitted to another human host during the next blood meal.

Recurrent and Persistent Infections

Recurrent malaria infection can occur in several ways. First, relapses from P. vivax or P. ovale can occur when dormant hypnozoites mature and release merozoites, thus producing blood-stage infections. Second, incomplete treatment or a partially effective host immune response can lead to low-concentration parasitemia and may lead to recrudescence of blood-stage infections. Relapse and recrudescence are caused by the same parasite clone that was responsible for the initial infection. Although recrudescence can occur with any malarial species, it is most common with P. falciparum because of antimalarial resistance. Finally, in areas of intense transmission, simultaneous infection or reinfection with multiple parasite species or strains can occur. P. malariae is frequently associated with persistent infections that can remain in the bloodstream at undetectable levels for up to 20 or 30 years.

Transmission

Natural transmission of malaria occurs through the bite of a female Anopheles mosquito. Blood-stage infection can also be established by transfusions of blood or blood products, by organ transplantation, or by sharing contaminated needles or syringes.^32,⁴⁵ Occasionally congenital malaria occurs when mothers of newborns are infected.^32,⁵⁴ It may be difficult to distinguish congenital malaria from natural mosquito-borne transmission when the diagnosis is made in neonates 2 to 3 weeks after birth.

Clinical Manifestations and Pathogenesis

Susceptible Populations

Patients with malaria present with variable and nonspecific signs and symptoms ranging from asymptomatic parasitemia to severe disease and death. Individuals living in malaria-endemic areas develop partial immunity through repeated infections with malaria parasites and rarely experience serious complications after childhood. Nonimmune individuals—such as travelers and immigrants from nonendemic areas, children from the age of 6 months to 5 years who are living in endemic areas, and pregnant women—are at risk for severe disease and complications, especially with P. falciparum infection.²

Major Clinical Findings

Clinical symptoms of malaria can develop as soon as 7 days to as late as several months after exposure in an area with endemic malaria. The majority of individuals who are diagnosed in the United States experience the onset of signs of symptoms after they return to the United States. A febrile illness in a traveler who has returned from a malaria-endemic area within the previous 3 months should be evaluated urgently.

Red blood cell lysis and the release of merozoites at the end of a period of intraerythrocytic asexual reproduction result in the classic presentation of a malarial paroxysm, which is characterized by high fevers, chills, rigors, sweats, and headache (Table 49-3). Without appropriate therapy, paroxysms can recur in a cyclic pattern (i.e., every 48 hours with P. vivax and P. ovale and every 72 hours with P. malariae). Although P. falciparum has a 48-hour asexual erythrocytic cycle, fever and chills typically occur without any periodicity, because erythrocyte lysis is not synchronized.

TABLE 49-3 Clinical Manifestations and Complications of Human Plasmodium Infection

Plasmodium Species	Manifestations and Complications
All species	Fever, chills, rigors, sweats, and headaches
	Weakness
	Myalgias
	Vomiting
	Diarrhea
	Hepatomegaly
	Splenomegaly
	Jaundice
	Anemia
	Thrombocytopenia
P. falciparum	Hyperparasitemia
	Cerebral malaria: seizures, obtundation, and coma
	Severe anemia
	Hypoglycemia
	Acidosis
	Renal failure
	Pulmonary edema (noncardiogenic)
	Vascular collapse
P. vivax and P. ovale	Splenic rupture
P. vivax and P. ovale	Relapse months to years after primary infection because of latent hepatic stages
P. malariae	Low-grade fever and fatigue
	Chronic asymptomatic parasitemia
	Immune complex glomerulonephritis

Patients with malaria infection may also present with generalized weakness, backache, myalgias, vomiting, diarrhea, and pallor. If an appropriate travel history is not obtained, malaria infection can be mistaken for a viral syndrome or acute gastroenteritis. In addition, severe malaria can mimic other diseases (e.g., meningitis, typhoid fever, dengue, hepatitis) that are common in malaria-endemic countries. Partially immune individuals who have recently arrived from endemic areas (e.g., immigrants, refugees) may be asymptomatic or have jaundice or signs of hepatosplenomegaly. Laboratory studies may reveal anemia and thrombocytopenia. Perinatal transmission of malaria is usually caused by P. falciparum and P. vivax. Clinical manifestations of congenital malaria can mimic neonatal sepsis and include fever, poor appetite, irritability, and lethargy.

Complications of P. Falciparum

Infection with P. falciparum has a greater risk for complications and death than infection with the other three human malarial species. First, P. falciparum can invade erythrocytes of all ages and thus produce overwhelming parasitemia. Second, red blood cells that are infected with P. falciparum adhere to endothelial cells, leading to microvascular pathology not observed with other malarial species.³⁴ Third, P. falciparum is frequently resistant to antimalarials (see Figures 49-1 and 49-2; Figure 49-1, online).

Travelers from nonendemic areas, children, and pregnant women are at greatest risk for developing complications from malaria infection. A person is considered to have complicated malaria when the manifesting signs include altered mental status, seizures, profound anemia, respiratory distress, gross hematuria, shock, or severe laboratory abnormalities, including hypoglycemia, acidosis, signs of disseminated intravascular coagulation, and hyperparasitemia (see Table 49-3). These are summarized as follows:

• Cerebral malaria: Acute neurologic events, such as seizures, obtundation, and coma, are associated with cerebral malaria. Cerebrospinal fluid examination is typically unremarkable, thus differentiating cerebral malaria from bacterial meningitis. Pathogenesis is a result of microvascular obstruction by parasitized erythrocytes, but neurologic impairment can result from multiple factors, including hypoglycemia, acidosis, impaired cerebral oxygenation from anemia, and pulmonary edema.^37,⁵⁰ The mortality rate can be as high as 15% to 30% in endemic areas, and higher in nonimmune adults (e.g., travelers). Children surviving episodes of cerebral malaria often have subtle cognitive and motor deficits.²⁸

• Severe anemia: Overwhelming parasitemia (i.e., >10 ⁶ parasitized red blood cells/µL or >20% parasitized circulating red blood cells) can develop rapidly in nonimmune individuals, resulting in severe anemia (i.e., hemoglobin level of <5 to 7 g/dL). The degree of parasitemia is always proportional to the degree of anemia. Moderate to low-grade parasitemia as well as persistent or recurrent infections in semi-immune individuals can lead to slow development of severe anemia. Factors contributing to development of anemia include red blood cell lysis and release of mature schizonts, suppression of erythropoietin by cytokines, and peripheral destruction of erythrocytes by the spleen.³⁴

• Metabolic complications: Nonimmune individuals are at risk for hypoglycemia and acidosis. Hypoglycemia can result from decreased oral intake, depletion of liver glycogen, parasite consumption of glucose, insulin release from the pancreas by quinine or quinidine, and inhibition of gluconeogenesis.^33,^44,⁵²

• Renal failure: The pathogenesis of renal failure may be multifactorial. These individuals have sequestration of parasitized erythrocytes in the cortex and findings consistent with acute tubular necrosis in the medulla. Other factors contributing to renal failure include hypotension, microvascular obstruction by P. falciparum–parasitized red blood cells, and free malarial pigment or heme.⁵² Renal failure is rare among children who are younger than 8 years old. Nonimmune individuals receiving treatment with quinine or quinidine may develop renal failure from massive hemolysis, resulting from overwhelming parasitemia and leading to free hemoglobin in the urine (i.e., blackwater fever).⁵¹

• Pulmonary edema: Late during the course of severe malaria, individuals can develop pulmonary edema with normal intrapulmonary and intracardiac pressures consistent with a capillary leak syndrome.^33,⁵² Sequestration of parasitized red blood cells is uncommon, and pulmonary edema is a rare complication among children.

• Diarrhea: Children living in malaria-endemic areas often present with watery diarrhea as a result of P. falciparum infection. This is thought to be secondary to sequestration of parasitized erythrocytes in the intestinal microvasculature. The precise mechanism is not known, but cytokines may also contribute to secretory diarrhea via tumor necrosis factor, prostaglandins, and cyclic adenosine monophosphate.

• Vascular collapse and shock: Individuals with severe malaria can develop vascular collapse and shock, which are often associated with adrenal insufficiency and hypothermia. Asplenic individuals are at increased risk for more severe disease and death.

Factors indicating a poor prognosis for persons with severe malaria include clinical, biochemical, and hematologic features (Table 49-4).^24,^43,⁵⁸ Poor clinical prognostic indicators include impaired consciousness, repeated convulsions, respiratory distress, bleeding, and shock. Biochemical indicators include renal impairment, acidosis, jaundice, hyperlactatemia, hypoglycemia, and elevated aminotransferases. Finally, hematologic features indicative of a poor prognosis include a hemoglobin level of less than 5 g/dL, parasitemia of more than 500,000 parasites per milliliter, greater than 10,000 mature trophozoites and schizonts per milliliter, or malaria pigment in at least 5% of neutrophils. A video clip of an African child with severe malaria can be accessed at http://video.who.int/streaming/malaria/severemalaria.wmv.⁶³

TABLE 49-4 Indicators of a Poor Prognosis with Severe Malaria

Indicator	Factor	Comments
Clinical	Age <3
	Impaired consciousness
	Seizures (≥3 in 24 hr)
	Absent corneal reflexes
	Papilledema
	Decerebrate or decorticate rigidity
	Opisthotonus
	Respiratory distress
	Shock
Biochemical	Hypoglycemia	Glucose <40 mg/dL
	Acidosis	Plasma bicarbonate <15 mmol/L
	Hyperlactatemia	Lactate >45 mg/dL
	Renal impairment	Serum creatinine >3 mg/dL; BUN >60 mg/dL
	Elevated aminotransferases	>3 times normal
	Hyperbilirubinemia	Serum total bilirubin >2.5 mg/dL
Hematologic	Hyperparasitemia	>500,000 parasites/mL or >10,000 mature trophozoites and schizonts/mL
	Anemia	Hemoglobin <5 g/dL; packed cell volume <15%
	Visible malarial pigment	>5% neutrophils with malarial pigment

BUN, Blood urea nitrogen.

Complications of P. Vivax and P. Ovale

Individuals with P. vivax infection typically present with fevers, chills, headaches, and myalgias, whereas individuals with P. ovale infection do not usually present with a toxic appearance. Anemia can result from acute P. vivax or P. ovale parasitemia. Anemia and splenomegaly are common among persons chronically infected with either P. vivax or P. ovale, and splenic rupture is an important late complication (see Table 49-3).²⁷ Because both P. vivax and P. ovale have a hepatic hypnozoite stage, symptoms may manifest months to years after the initial infection.

P. vivax invades reticulocytes, resulting in lower levels of parasitemia than those seen with P. falciparum infection. Cytoadherence does not occur with P. vivax or P. ovale. Thus, all stages of the parasite circulate in the peripheral blood, and microvascular changes associated with sequestration in deep vascular beds are not observed. Individuals lacking expression of the Duffy blood group antigen (e.g., many Africans) are protected from P. vivax infection, because this antigen is used as a receptor for erythrocyte invasion by the P. vivax parasite.³⁶

Complications of P. Malariae

Because P. malariae produces persistent low-level parasitemia, it usually manifests with mild symptoms such as weakness, low-grade fever, and fatigue. Individuals can have chronic asymptomatic parasitemia for years. This can be associated with an immune complex glomerulonephritis, where complement-fixing antibodies are directed against P. malariae antigens.¹⁸

Diagnosis

History

The most important factor for early and prompt diagnosis of malaria, particularly in nonendemic areas, is for the health care provider to consider it in the differential diagnosis of a febrile patient with appropriate travel history. Most imported malaria cases in the United States occur among travelers who have visited friends or relatives in malaria-endemic areas.³² Because of the risk of complications and death, fever in the returned traveler should be taken seriously. A thorough travel history must be obtained, including travel dates, destinations, and any chemoprophylaxis taken.^30,⁵⁷ As a result of drug resistance and the possibility of inadequate adherence to medication schedules, a history of chemoprophylaxis use in a returned traveler does not exclude a diagnosis of malaria. The patient may not have the typical malarial paroxysms of fever and chills. Nonspecific symptoms such as fatigue, diarrhea, headache, myalgias, and sore throat may lead to another diagnosis. Fever and persistent malaise may occur among semi-immune individuals.